Thiazoline analgesics



This invention relates to a therapeutic composition and a process of treatment and more particularly to therapeutic compositions having analgetic and antipyretic properties and the process of using the said compositions for treatment. A wide variety of substances and compositions have been used for the relief of pain. These agents have been classified as general anesthetics when pain is relieved by causing a loss of consciousness, hypnotics when pain is relieved by inducing sleep, and analgetics when pain is relieved by raising the threshold of the subjects awareness of the pain without affecting mental alacrity or reducing skeletal muscle activity.

The analgetic agent is by far the most commonly used type. Aspirin, sodium salicylate, acetophenetidin, sali cylamide and Nacetyl-p-aminophenol are commonly available analgetics having theadvantages of being readily available and substantially safe to use. These analgetics have a disadvantage however in not having a strong action. Codeine which is a very efiective analgesic has a particularly undesirable side effect of being addicting.

It has therefore been an objective of pharmaceutical research to produce a new analgesic composition that would be the'fideal analgesic. This ideal analgesic is generally agreed to be one that is at least as efiective as codeine and is no more toxic than aspirin. Until the ideal is obtained the art advances by producing new compositions having increasing eifeetiveness and decreasing toxicity. Similarly, it is the object to relieve the subjective pain without causing a disruption in the proper functioning of the organism. V

The present invention comprises the process of admin istering and the compositions comprising a member selectedfromthe group consisting of compounds having the formula i it XO\ /CNH2 on, s (Formulal) wherein R methylene (CH ethylene *CH CH and ethylidene (3H3 and X is methyl (CH and hydrogen H), including the acid addition salts thereof of pharmacologically acceptable acids, in association with a pharmaceutical carrier. 7

The administration of the compositions of the present invention provides the veterinarian with a process for inducing a state of analgesia in the animal to whom the composition is administered. Advantageously this state of analgesia is attained by the administration of the compositions of the present invention without producing unconsciousness, stupefaction, toxicity or addiction in the subject. Compared on a mg. to mg. basis, the compounds of the Formula I of the present invention are capable of raising the pain threshold in the subject to about the same degree as codeine. However, unlike codeine, the compounds are not addicting.

" are The compositions of the present invention are also antipyretic in that they are capable of reducing the body temperature.

The compositions of the present invention are presented for oral administration in solid and liquid unit dosage forms, such as tablets, capsules, powders, granules, syrups, elixirs and the like, containing suitable quantities of the compound of Formula I.

Powders are quite simply prepared by comminuting a compound of the Formula I to a suitably fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrohydrate material such as starch. Advantageously, a sweetening agent or sugar is present as well as a flavoring oil.

Granulations are prepared utilizing water-soluble diluents. A powder mixture of finely divided compound of Formula I, in the form of a Water-soluble salt, and a.

water-soluble diluent such as sucrose, glucose, and the like, is wetted with a binder such as acacia mucilage or gelatin solution and forced through a screen to form granules which are allowed to dry. Effervescent granules are prepared utilizing a fruit acid, such as citric acid and/or tartaric acid and sodium bicarbonate.

Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths. Advantageously, as an adjuvant to the filling operation, a lubricant such as talc, magnesium stearate and calcium stearate is added to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture, gran-' ulating or slugging, adding a lubricant and pressing into tablets. The powder mixture is prepared by mixing a compound of the Formula I, suitably comminuted, with a. diluent or base such asstarch, lactose, kaolin, dicalciurn phosphate and the like. The powder mixture can be granulated by wetting with a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and forcing through a screen. As an alternative to granulating, the powder mixture can be slugged, i.e., run through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs). The slugs can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.

Advantageously the tablet can be provided with a protective coating consisting of a sealing coat of shellac, a coating of sugar and methylcellulose and a polish coating of carnauba Wax.

Oral fluids are prepared in unit dosage forms such as syrups and elixirs wherein each teaspoontul of composition contains a predetermined amount of a compound of Formula I for administration.

A syrup is prepared by dissolving the compound of Formula I in a suitably fiavored aqueous sucrose solution. Similarly an elixir is prepared utilizing a hydroalcoholic vehicle. Elixirs are advantageous vehicles for use when another therapeutic agent which is not sutficiently water soluble is to be included in the composition.

For parenteral administration aqueous fluid unit dosage forms can be prepared. In preparing the parenteral form, a measured amount of a compound of Formula I is placed in a vial, the vial and its contents sterilized and sealed. An accompanying vial of sterile water is provided as a solvent to form a solution prior to administration. Advantageously the sterile water can have dissolved therein a local anesthetic and buffering agents. "Alternatively, a parenteral solution can be prepared by dissolving a compound of the Formula I in water, with or without additional adjuvants, and filter sterilizing before filling into sterile vials.

In addition to oral and parenteral administration, the

can be repeated in 3-4 3 to 30 grains of the compound of Formula I (:J rectal route can be utilized. The compound of Formula I can be administered by means of a suppository. A vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized. For example, cocoa butter and various polyethylene glycols can serve as the vehicle.

For the treatment of domestic birds and animals by oral administration, the compound of Formula I is conveniently prepared in the form of a food premix. The food premix can comprise the compound of formula I in admixture with an edible pharmaceutical diluent of the type previously mentioned such as starch, oatmeal,

flour, calcium carbonate, talc, dried fish meal and the like non-toxic, orally acceptable pharmaceutical diluents. The prepared premix is then conveniently added to the regular feed, thereby providing medication to the animal or bird in the course of feeding.

The term unit dosage form as used in the specification and claims refers to physically discrete units suitable as unitary dosages for animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in associationwith the required pharmaceutical diluent, carrier or vehicle. The specification for the novel unit dosage forms of this invention is dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in animals, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, troches, powder packets,

granules, wafers, cachets, segregated multiples of any of the foregoing and other forms as herein described.

In addition to the administration of a compound of the Formula I as the principal active ingredient of compositions for the treatment of the conditions described herein, the said compound can be included with other types of compounds to obtain advantageous combinations of properties. Such combinations can include a compound of the Formula I in combination with other analgetic agents such as codeine, aspirin, acetophenetidin, salicylamide and N-acetyl-p-aminophenol; hypnotic agents such as the barbiturates and chloral hydrate; steroids such as hydrocortisone, prednisolone and methylprednisolone; muscle relaxants such as chlorzoxazone, carisoprodol, mephenesin, meprobarnate, phenaglycodol and zoxazolamine; and antihistamines such as chlorpheniramine maleate, thenylpyramine fumarate, prophenpyridamine, and pyrilamine.

The amount of a compound of the Formula I that is to be administered depends on the age, weight of the patient, the particular condition to be treated and the route of administration. A dose of from about 0.5 to about 1 mg. per kg. of body weight given as a singledose, which hours, embraces the preferred dosage range for the treatment of most conditions for which the said compounds are etiective.

For example, in the treating of horses sulfering from tendonitis, muscular soreness or laminitis a dose of from can be administered.

The compound of the Formula I is compounded with a suitable pharmaceutical diluent in unit dosage form for convenient and eltective administration; in a preferred embodiment of this invention, a unit dosage form containing a compound of the Formula I in an amount of from about 8 mg. to about 65 mg. is administered. Expressed in terms of concentration, a compound of the Formula I can be present in the compositions for the present invention in a concentration of from about 0.2% to about 10% w./w. of the composition. The dosage of compositions containing a compound of the Formula I and one or more othertactive ingredients is d to be determined with reference to the usual dosage of each such ingredient.

PREPARATION I Z-amin0-5,6-dihydro-6-metlzyl-4H-1,S-thiazine and acid addition salts thereof A. 2-AMINO-5,GDIHYDRO-(i METHYLdH-l,3-THIAZINE A mixture consisting of 2.0 gm. of 1-(3-tbutenyl)-2- thiourea (Kjaer et al., Acta Chem. Scand. 7: 518527 [1953]) and 35.0 ml. of 12 M-hydrochloric acid was heated in a closed pressure tube at about l00 C. for 3.5 11r., after which water and hydrogen chloride were removed by distillation under reduced pressure. The residue was treated with aqueous potassium hydroxide solution and the mixture Was extracted with ether. The ether extract was Washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and evaporated to dryness by distillation under reduced pressure. There was thus obtained 1.8 gm. of oily 2-amino- 5,6-dihydro-6-methyl-4H-1,3-thiazine.

B. 2-AMINO-5,6-DIHYDRO-6-METHYL-4H-1,8- IHIAZINE CYCLOHEXANE SULFAMATE Equimolar amounts of 2-amino-5,6-dihydro-oamethyl 4H-l,3-thiazine and cyclohexansulfamic acid were dis solved in absolute ethanol. Ether was added to cause precipitation ofsolid material, which was isolated by iiitrait-ion of the mixture and was then recrystallized from ethanol-ether mixture. There was thereby obtained 2 amino-5,6-dihydro-6-methyl-4I-l-1,3-thiazine cyclohexane sulfamate having a melting point of 168 to 169 C.

Analysis-Calm. 01 C11H23N303S2: C, H, 7.49. Found: C, 42.97; H, 7.41.

By replacing cyclohexanesulfamic acid with hydrochloric acid, hydrobromic acid, acid, acetic acid, benzoic acid, salicyclic acid, maleic acid, citric acid, succinic acid, and tartaric acid, there are ob tained 2-amino-5,6-dihydro-6rnethyl-4H-1,3-thiazine hydrohloride, hydrobromide, sulfate, phosphate, acetate, benzoate, salicylate, maleate, citrate, succinate and tar tratc, respectively.

Other members of the group of compounds of Formula I are known in the art. For example: 2arnino-5-methyl- Z-thiazoline,Beilstei-n, vol. 27, 1st Supp, rp..26l;rvol. 27,

p. 14 6; Z-amino-S,5-dimethyl-2-thiazoline, Dawson and Eastes, I. Am. Chem. Soc. 59, p. 2012 (1937); and 2- amino-4,S-dimethyl-Z-thiazoline, Beilstein, vol. 27, p. 153.

EXAMPLE 1 One thousand tablets for oral administration, each containing 16.2 mg. 4 grain) of 2-amino-5-methyl-2-thiazoline hydrochloride and 48.6 mg. grain) of'cyclopentenylallylbarbituric acid, are prepared from the following types and amounts of ingredients:

Gm. 2-amino-5-methyl-2 thiazoline hydrochloride 16.2 Cyclopentenylallylbarbituric acid- 48.6 Lactose 75 Starch 65 Magnesium stearate 15 EXAMPLE 2 One thousand tablets for oral administration, each containing 32.4 mg. A2 grain) of Z-amino-S-methyl-Z-thiazoline hydrochloride and 2 mg. of 6-methyl-delta-1-hydrocortisone, are prepared from the following types and amounts of ingredients:

sulfuric acid, phosphoric Gm. 2-amino-5-methyl-2 thiazoline hydrochloride 32.4 fi-methyl-delta-l-hydrocortisone 2 Lactose 75 Starch 65 Calcium stea-rate 2..

The ingredients are thoroughly mixed and slugged. 'Ihe slugs are broken down by forcing through a, screen and the resulting granules are then compressed into tablets, each tablet containing 32.4 mg. of Z- 'amino-S-methyl- Z-thiazoline hydrochloride and 2 mg. of 6-methyl-deltal-hydrocortisone.

EXAMPLE 3 One thousand tablets for oral administration, each containing 64.8 mg. (1 grain) of 2-amino-5-methyl-2-thiazoline hydrochloride, are-prepared [from the following types and amounts of ingredients:

- vGm. Z-amino-S- methyl-Zthiazoline hydrochloride 64.8 Lactose 100 Cornstarch 65 Magnesium stearate 15 .The ingredients are thoroughly mixed and slugged.

The slugs are broken down by forcing through a No. 16 screen. The resulting granules are then compressed into tablets, each tablet containing 64.8 mg. (1 grain) of 2- amino-5-methyl-2-thiazoline hydrochloride. Following the foregoing procedure tablets are similarly prepared containing 2-amino-S-methyl-Zathiazoline hydrochloride in 8.1 mg. A2 grain), 16.2 mg. A grain), and 32.4 mg. A2 gratin), amounts by substituting 8.1, 16.2, and 32.4 gm. amounts of 2-amino-5-methyl-2-thiazoline hydrochloride for the 64.8 gm. amount of the example.

EXAMPLE 4 One thousand capsules for oral administration are prepared from the following types and amounts of ingredients:

' Gm. Z-amino-5-methyl-2-thiazoline hydrochloride 32.4 Acetophenetidin 162 Acetylsalicyclic acid 227 Caffeine 32.4

Hard gelatin capsules No. l.

The ingredients are mixed until uniformly blended and then filled into hard gelatin capsules, each capsule containing: 2-amino-5-methyl 2 thiazoline hydrochloride, 32.4 gm. /2 grain); acetophenetidin, 162 mg. (2 /2 grains); acetylsalicylic acid 227 mg. (3 /2 grains); and cafieine, 32.4 mg. /2 grain).

EXAMPLE 5 One thousand cc. of an elixir, containing 16.2 mg. of

2-amino-5-methyl-2-thiazoline hydrochloride and 8.1 mg.

of phenobarbital in each 5 cc., is prepared from the following types and amounts of ingredients:

The sugar is dissolved in 450 cc. of water and the citric acid, color, and 2-arnino-5-methyl-2-thiazoline hydrochloride added thereto. The phenobarbital and saccharin are added to the mixture of alcohol and glycerin and stirred until dissolved, followed by the flavors previously mixed with the polysorbate 80.

, 2-amino-S-methyl-Z-thiazoline hydrochloride gm 32.4 Chlorobutanol --grn-.. 5 Water for injection cc '1000 The sugar and alcohol solutions are mixed and sufiicient water is finally added to make 1000 cc.

EXAMPLE 6 A sterile aqueous solution for parenteral administration, containing 32.4 mg. of 2 amino-5-rnethyl-2-thiazoline hydrochloride in each cc., is prepared from the following types and amounts of ingredients:

The Z-amino-S-methyl-Z-thiazoline hydrochloride and chlorobutanol are dissolved in the water for injection and the solution sterilized by filtration. The sterile solution is filled into 2 cc. sterile vials and sealed.

EXAMPLE 7 One thousand capsules for oral administration, each capsule containing 1 mg. of 6a-methylprednisolone, 300 mg. of aspirin, 200 mg. of calcium carbonate and 16.2 mg. of 2-amino-5-methyl-2-thiazoline, are prepared from the following types and amounts of ingredients:

Gm. 2-amino-5-methyl-2-thiazoline hydrochloride 16.2 6a-methylprednisolone 1 Aspirin 300 Calcium carbonate 200 The powdered ingredients are thoroughly mixed and filled into hard gelatin capsules of suitable size.

EXAMPLE 8 One thousand capsules for oral administration, each containing 16.2 mg. grain) of 2-amino-5-rnethyl-2- thiazoline hydrochloride, 2 mg. of chlorpheniramine maleate, 25 mg. of methoxyphenamine hydrochloride, 162 mg. (2 /2 grains) of acetophenetidin, 226.8 mg. (3 /2 grains) of aspirin and 32.4 mg. /2 grain) of caffeine, are prepared from the following types and amounts of ingredients:

Gm. 2-amino-5-methyl-2-thiazoline hydrochloride 16.2 Chlorpheniramine maleate 2 Methoxyphenamine hydrochloride 25 Acetophenetidin 162 Aspirin 226.8 Caffeine 32.4-

The powdered ingredients are thoroughly mixed and filled into hard-gelatin capsules of suitable size.

EXAMPLE 9 1000 cc. of a medicated syrup, containing 8.1 mg. (/8 grain) of 2-amino-5-methyl-2-thiazoline hydrochloride in each 5 cc., is prepared from the following types and amounts of ingredients:

2-amino-S-methyl-Z-thiazoline hydrochloride gm 1.62 Elixir terpin hydrate, NF XI, q.s cc 1000 EXAMPLE 10 Following the procedure of the preceding Examples 1 through 9, inclusive, compositions are prepared substituting equivalent amounts of the 2-amino-5-methyl-2- thiazoline firee base for the hydrochloride salt of the examples. Similarly, compositions can be prepared using other salts: equivalent amounts of the hydrobromide, sulfate, phosphate, acetate, benzoate, salicylate, maleate,

citrate, tartrate and succinate, respectively are used in place of the hydrochloride in each of the examples.

EXAMPLE 11 Following the procedure of the preceding Examples 1 through 9, inclusive, compositions are prepared substituting equivalent amounts of 2-amino-5,5-dimethyl-2- thiazoline, 2-amino-4,S-dimethyl-Z-thiazoline, Z-amino-S, 6-dihydro-6-methyl-4H-l,S-thiazine, and the hydrochloride, hydrobromide, sulfate, phosphate, acetate, benzoate,

a s alicylate, maleate, citrate, tartrate and succinate salts of each of the foregoing compounds for the Z-amino-Z-methyI-Z-thiazoline hydrochloride of each of the examples.

What is claimed is:

. 1. A process for inducing a state of analgesia comprising the administration to an animal in a state of pain of a compound selected from the group consisting of compounds having the formula:

wherein R is a member selected from the group consisting of methylene, ethylene and ethylidene and X is a member selected from the group consisting of methyl and hydrogen and the salts of pharmacologically acceptable acids thereof.

2. A process for raising the pain threshold comprising the administration of a compound selected from the group consisting of compounds having the formula:

wherein R is a member selected from the group consistwherein R is a member selected from the group consisting of methylene, ethylene and ethylidene and X is a member selected from the group consisting of methyl and hydrogen, and the salts of pharmacologically acceptable acids thereo, in association with a pharmaceutical carrier.

References Cited in the file of this patent UNITED STATES PATENTS 2,780,577 Phillips Feb. 5, 1957 2,783,229 Tummcs Feb. 26, 1957 2,871,238 Gregory Jan. 27, 1960 2,881,169 Whittingham Apr. 7, 1960 2,953,494

Cook Sept. 20, 1960 

1. A PROCESS FOR INDUCING A STATE OF ANALGESIA COMPRISING THE ADMINISTRATION TO AN ANIMAL IN A STATE OF PAIN OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: 